Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST)

Daniels, Marc; Lurkin, Irene; Pauli, R.; Erbstösser, E; Hildebrandt, Uwe; Hellwig, Karsten; Zschille, Uwe; Lüders, Petra; Krüger, Gabriele; Knolle, J.; Stengel, Bernd; Prall, Friedrich; Hertel, K.; Lobeck, H.; Popp, Brigitte; Theissig, F; Wünsch, Peter H.; Zwarthoff, Ellen C.; Agaimy, Abbas; Schneider‐Stock, Regine

doi:10.1016/j.canlet.2011.07.029

Cited by 124 publications

(95 citation statements)

References 42 publications

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“…These frequencies are lower for KIT and higher for PDGFRA than the same mutations observed in non gastric GISTs, 4,5,7,10,21,28 in agreement with results from other studies. Miettinen et al 14 observed a 22.6% incidence of PDGFRA mutations in a series of gastric GISTs, while Wasag et al 29 reported that all PDGFRA mutations (25%) found in their GIST case series were observed in gastric GISTs.…”

Section: Discussionsupporting

confidence: 92%

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Capelli

Petracci

Quagliuolo

et al. 2016

European Journal of Surgical Oncology (EJSO)

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Background: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinicalepathological characteristics and prognosis. Methods: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinicalepathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. Results: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions

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Section: Discussionsupporting

confidence: 92%

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Capelli

Petracci

Quagliuolo

et al. 2016

European Journal of Surgical Oncology (EJSO)

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“…5,6 Recently, PIK3CA mutations have been reported in two primary gastric GISTs: one concurrent with a KIT mutation and another with the HRAS mutation, and in treatment-resistant metastasis of a BRAF-mutant GIST. [7][8][9] Thus, activation of the PI3K/AKT/mTOR signaling pathway may have a role in both pathogenesis and the progression of GISTs. The presence of the PIK3CA mutation could indicate an alternative treatment inhibiting the PI3K/AKT/ mTOR signaling pathway for patients with advanced and metastatic tumors, as opposed to KIT inhibitor therapy.…”

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confidence: 99%

Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases

et al. 2016

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Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors usually driven by the mutational activation of receptor tyrosine kinases, KIT, or PDGFRA. Oncogenic activation of phosphatidylinositide-3-kinase (PI3K), a downstream effector in the KIT signaling pathway, has been identified in different types of cancer, with the PI3K 110α subunit encoded by PIK3CA being a common mutational target. In this study, the mutational hotspot in the PIK3CA kinase domain encoded by exon 20 was evaluated in 529 imatinib-naive GISTs using PCR amplification and Sanger sequencing. Eight mutations (two co-existing in one tumor) were identified. Subsequently, The cobas PIK3CA Mutation Test was employed to evaluate mutational hotspots in exons 1, 4, 7, and 9 in 119 PIK3CA exon 20-wild type tumors. In two cases, mutations in exons 1 and 9 were identified. In one GIST, previously undetected by Sanger sequencing, the exon 20 mutation was discovered. Altogether, eight primary and two metastatic GISTs carried PIK3CA mutations. The size of primary PIK3CA-mutant GISTs was ≥ 14 cm (mean size 17 cm), and mitotic activity varied from 0 to 72 per 50HPF (mean 5/50HPF). Follow-up data showed short survival in 6 of 7 studied cases. Detection of PIK3CA mutations in large or metastatic KIT-mutant GISTs may suggest that PIK3CA-mutant clones have a proliferative advantage during disease progression. Tyrosine kinase inhibitors have been successfully used in GIST treatment. However, resistance frequently develops due to secondary KIT mutations or activation of downstream to KIT signaling pathways, such as the PI3K/AKT/mTOR pathway. PIK3CA mutations similar to the ones detected in GISTs have been shown to cause such activation. Therefore, genotyping of PIK3CA in GISTs might help to pinpoint primary and metastatic tumors with the potential to develop resistance to tyrosine kinase inhibitors and guide therapy with PI3K inhibitors.

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“…A recent paper by Lasota et al reported about the absence of KRAS mutations in a large cohort of GISTs (n =514) [3] which, to the best of our knowledge, constitutes by itself about 60 % of cases so far studied for this molecular alteration [4][5][6][7]. Thus, considering the cumulative evidence produced so far, the actual possible prevalence of KRAS mutations in GISTs seems much lower than the one we hypothesized, possibly approaching 0.3 %.…”

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confidence: 50%

On the prevalence of KRAS mutations in GISTs

2013

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Dear Editor, In our commentary entitled "GISTogram: a graphic presentation of the growing GIST complexity," recently published in Virchows Archiv [1], on the basis of an extrapolation from a naïve GIST cohort from Ticino, Switzerland [2], we proposed a possible 4 % prevalence of KRAS mutations in GISTs. A recent paper by Lasota et al. reported about the absence of KRAS mutations in a large cohort of GISTs (n =514) [3] which, to the best of our knowledge, constitutes by itself about 60 % of cases so far studied for this molecular alteration [4][5][6][7]. Thus, considering the cumulative evidence produced so far, the actual possible prevalence of KRAS mutations in GISTs seems much lower than the one we hypothesized, possibly approaching 0.3 %.

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Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST)

Cited by 124 publications

References 42 publications

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases

On the prevalence of KRAS mutations in GISTs

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